Article

Analysis of the Illicit Opioid U-48800 and Related Compounds by LC–MS-MS and Case Series of Fatalities Involving U-48800

Authors:
  • Center for Forensic Science Research and Education
  • Center for Forensic Science Research and Education
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Abstract

We report a method for the detection and quantitation of 12 drugs and 2 metabolites in the same structural class as the illicit mu-opioid agonist U-47700 in human whole blood. These substances are either known or suspected to be present as potential novel opioids in illicit drug markets. The general class of these drugs was developed in pharmaceutical research programs in the 1970s, but these drugs have recently become of concern for overdoses and death in opioid users in the USA and internationally. The scope of analysis included the following compounds: methylenedioxy U-47700, ethylenedioxy U-47700, ethylenedioxy U-51754, U-69593, U-47931E (bromadoline), U-47700, U-48800, U-49900, U-51754, U-50488, propyl U-47700 and isopropyl U-47700. Additionally, two metabolites N,N-didesmethyl U-47700 and desmethyl U-47700 were also included in the scope. Drugs were extracted from human whole blood using solid-phase extraction, and the extracts were analyzed by liquid chromatography tandem mass spectrometry. The assay was validated with respect to bias, carryover, interference, within-run and between-run precision, and accuracy. Eight medicolegal death investigation cases that had screened positive for U-48800 by liquid chromatography time-of-flight mass spectrometry were successfully confirmed and quantified using this method. The mean and median concentrations of U-48800 in these cases were 2.5 (±2.1) and 1.8 ng/mL, respectively, with a range of concentrations of 0.27–6.2 ng/mL. Case history information including the presence of other drugs in combination are described and discussed.

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... Among U-and AH-compounds, only U-47700, U-48800, and AH-7921 were reported to cause human deaths (Table 1) [14,20,22]. ...
... In vitro-binding affinities (EC 50 Analytical methods for the U-compounds have been well studied [22][23][24][25][26][27][28][29] including pretreatments and instrumental analyses by liquid chromatography (LC)-tandem mass spectrometry (MS/MS), ultra-high-performance liquid chromatography (UHPLC)−MS/MS, UHPLC−high-resolution mass spectrometry (MS), LC−quadrupole time-of-flight-MS, and gas chromatography−MS. The pretreatments are mainly conventional liquid-liquid (L-L) extraction and solid-phase extraction (SPE). ...
... Table 1 shows that U-47700, AH-7921, and MT-45 caused relatively many deaths, although all toxicities/potencies were not so high. It should be mentioned that U-48800 caused at least 8 deaths despite the action as a κ opioid receptor agonist [22]. MT-45 is less potent than morphine (Table 1), but it caused at least 30 deaths; although MT-45 is less potent than morphine as a μ opioid receptor agonist, its metabolic product M1 was reported to antagonize N-methyl-d-aspartate receptor with the risk of fatality [48]. ...
Article
Purpose: Since the appearance of fentanyl followed by its many kinds of analogues around 1988, North America has been exposed to fierce synthetic opioid pandemic resulting in more than 130,000 deaths due to their overdoses until May 2019, when China declared to prohibit the licit fentanyl analog production. However, the Chinese announcement did not go into force in USA due to the adroit strategies of tough traffickers. Thus, contrary to the expectation, the number of synthetic opioid products and their poisoning cases in USA has increased by about 30%; especially, various benzimidazole synthetic opioids have revived on the illicit drug market during a recent few years. In this article, the recent abrupt changes in the situations of illicit synthetic opioid market and their current abuses are described. Methods: Various databases, such as SciFinder, Google, and Google Scholar, were utilized to collect relevant reports referring old but newly appearing synthetic opioids. Results: At the present time, there are several families of new synthetic opioids, which are not fentanyl derivatives; MT-45 and its analogs, benzamide and 2-phenylacetamide opioids (U-series opioids), and benzimidazole opioids. Most of the above substances had been developed in 1950s to 1970s, but had never been used as analgesic medicines, because of their severe adverse effects, such as respiratory depression, physical dependence, and resulting deaths. However, there is possibility that these drugs will become main illicit synthetic opioids in place of the fentanyl analogs during coming several years from this time. Conclusions: All of the above non-fentanyl-derived families had been developed 50-70 years ago to establish them as analgesic medicines, but had been unsuccessful. These drugs largely appeared in the illicit drug markets in North America, Europe, and Australia, during recent years. Pharmacological, toxicological, and metabolic studies are insufficient for benzamide and 2-phenylacetamide opioids, and are very scant especially for benzimidazole opioids. This time we should start studying pharmacotoxicology of the newly emerging synthetic opioids to alert forensic toxicologists in the world and to suppress their rapid and wide spread in the world. Supplementary information: The online version contains supplementary material available at 10.1007/s11419-022-00624-y.
... Adulterants are pharmacologically active substances added to mirror or enhance specific drug effects [30] and have been well-described in illicit drug supply studies. Adulterants in heroin have included scopolamine [31] and quinine [32,33], and more recently clenbuterol [34,35] and novel synthetic opioids [36,37]. Recent reports have described the adulterant role of xylazine as one that improves and prolongs opioid-associated euphoria [9]. ...
Article
Introduction: Illicit opioids, consisting largely of fentanyl, novel synthetic opioids, and adulterants, are the primary cause of drug overdose fatality in the United States. Xylazine, an alpha-2 adrenergic agonist and veterinary tranquilizer, is being increasingly detected among decedents following illicit opioid overdose. Clinical outcomes in non-fatal overdose involving xylazine are unexplored. Therefore, among emergency department patients with illicit opioid overdose, we evaluated clinical outcome differences for patients with and without xylazine exposures. Methods: This multicenter, prospective cohort study enrolled adult patients with opioid overdose who presented to one of nine United States emergency departments between 21 September 2020, and 17 August 2021. Patients with opioid overdose were screened and included if they tested positive for an illicit opioid (heroin, fentanyl, fentanyl analog, or novel synthetic opioid) or xylazine. Patient serum was analyzed via liquid chromatography quadrupole time-of-flight mass spectroscopy to detect current illicit opioids, novel synthetic opioids, xylazine and adulterants. Overdose severity surrogate outcomes were: (a) cardiac arrest requiring cardiopulmonary resuscitation (primary); and (b) coma within 4 h of arrival (secondary). Results: Three hundred and twenty-one patients met inclusion criteria: 90 tested positive for xylazine and 231 were negative. The primary outcome occurred in 37 patients, and the secondary outcome occurred in 111 patients. Using multivariable regression analysis, patients positive for xylazine had significantly lower adjusted odds of cardiac arrest (adjusted OR 0.30, 95% CI 0.10-0.92) and coma (adjusted OR 0.52, 95% CI 0.29-0.94). Conclusions: In this large multicenter cohort, cardiac arrest and coma in emergency department patients with illicit opioid overdose were significantly less severe in those testing positive for xylazine.
... In the case of sample 3E, it is, for some services, impossible to differentiate between structural analogues, as the two molecules, U-48800 and U-51754 (see Figure 2), differ only in the position of a chloride atom (regioisomers) [35,36]. In this case, services should have access to nuclear magnetic resonance (NMR) analysis, e.g., through collaboration with a university laboratory or governmental laboratory [37][38][39]. ...
Article
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Background: Drug checking is a proven harm reduction strategy and provides real-time information on the market of new psychoactive substances (NPS). It combines chemical analysis of samples with direct engagement with people who use drugs (PWUD), giving the ability to increase preparedness and responsiveness towards NPS. Next to that, it supports rapid identification of potential unwitting consumption. However, NPS cause a toxicological battle for the researchers, as factors such as the unpredictability and quick shift of the market complicate the detection. Methods: To evaluate challenges posed towards drug checking services, proficiency testing was set up to evaluate existing analytical techniques and investigate the capability to correctly identify circulating NPS. Twenty blind substances, covering the most common categories of substances, were analyzed according to the existing protocols of the existing drug checking services, including several analytical methods such as gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with diode array detector (LC-DAD). Results: The proficiency test scores range from 80 to 97.5% accuracy. The most common issues and errors are mainly unidentified compounds, presumably due to no up-to-date libraries, and/ or confusion between structural isomers, such as 3- and 4-chloroethcathinone, or structural analogs, such as MIPLA (N-methyl-N-isopropyl lysergamide) and LSD (D-lysergic acid diethylamide). Conclusions: The participating drug checking services have access to adequate analytical tools to provide feedback to drug users and provide up-to-date information on NPS.
... U-49900 does not have good reviews in drug forums because of its foul odor and little efficacy [16]. A few reports include U-48800 as a drug seized recently responsible for several fatalities [17]. It is expected that other members of this group will soon be incorporated into the growing number of NPS. ...
Chapter
The last decade has seen a significant increase in synthetic opioids among the new psychoactive substances (NSP). The first two sections of this chapter review the different opioids pertaining to this group and the main effects of the opioid drugs recently incorporated into the NPS or currently in use. The third section examines the precursor and pre-precursors needed to synthesize opioids and how they are regulated. The fourth section analyzes the role of the public Internet, the darknet, cryptocurrencies, and postal services in NPS trading. Finally, the last section presents some challenges these substances pose to prevention and regulation policies and the strategies proposed to face them.KeywordsNew psychoactive substances (NPS)DarknetCryptocurrenciesRegulationPrevention
... Baumann et al. evaluated the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection and forensic toxicology pharmacology of U-47700 and its analogs and postulated that the reason U-47700 was the only drug to gain traction in US illicit markets was because of its higher potency compared to other drugs in the series (340). A subsequent case series involving U-48800 was published (239). ...
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An important role of modern forensic and clinical toxicologists is to monitor the adverse events of novel psychoactive substances (NPS). Following a prior review from 2013-2016, this critical literature review analyzes and evaluates published case reports for NPS from January 2017 through December 2020. The primary objective of this study is to assist in the assessment and interpretation of these cases as well as provide references for confirmation methods. Chemistry, pharmacology, adverse events, and user profiles (e.g., polypharmacy) for NPS are provided including case history, clinical symptoms, autopsy findings, and analytical results. Literature reviews were performed in PubMed and Google Scholar for publications using search terms such as NPS specific names, general terms (e.g., "designer drugs," "novel psychoactive substances"), drug classes (e.g., "designer stimulants,"), and outcome-based terms (e.g., "overdose," "death"). Government and website drug surveillance databases and abstracts published by professional forensic science organizations were also searched. Toxicological data and detailed case information were extracted, tabulated, analyzed, and organized by drug category. Case reports included overdose fatalities (378 cases), clinical treatment and hospitalization (771 cases), and driving under the influence of drugs (170 cases) for a total of 1,319 cases providing details of adverse events associated with NPS. Confirmed adverse events with associated toxidromes of more than 60 NPS were reported to include synthetic cannabinoid, NPS stimulant, NPS hallucinogen, NPS benzodiazepine, and NPS opioid cases. Fifty of these NPS were reported for the first time in January 2017 through December 2020 as compared to the previous four years surveyed. This study provides insight and context of case findings described in the literature and in digital government surveillance databases and websites during a recent four-year period. This review will increase awareness of adverse events associated with NPS use to better characterize international emerging drug threats.
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Isolated organ models are a versatile tool for pharmacological and toxicological research. Small bowel has been used to assess the inhibition of smooth muscle contraction by opioids. In the present study, we set out to establish a pharmacologically stimulated rat bowel model. The effects of carfentanil, remifentanil and the new synthetic opioid U-48800 and their respective antagonists naloxone, nalmefene and naltrexone were studied in a small bowel model in rats. The IC50 values of the tested opioids were as follows: carfentanil (IC50 = 0.02 µmol/L, CI 0.02-0.03 µmol/L) ≫ remifentanil (IC50 = 0.51 µmol/L, CI 0.40-0.66 µmol/L) ≫ U-48800 (IC50 = 1.36 µmol/L, CI 1.20-1.54 µmol/L). The administration of the opioid receptor antagonists naloxone, naltrexone and nalmefene led to progressive, parallel rightward shifts of the dose-response curves. Naltrexone was most potent in antagonizing the effects of U-48800, whereas naltrexone and nalmefene were most effective in antagonizing the effects of carfentanil. In summary, the current model seems to be a robust tool to study opioid effects in a small bowel model without the necessity of using electrical stimulation.
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Over the last decade, there has been a significant growth in the market and number of new psychoactive substances (NPS). One of the NPS groups that has grown rapidly in recent years, bringing a new set of problems, consists of new synthetic opioids. The extreme potency of these compounds poses a high risk of acute poisoning, as an overdose can cause respiratory depression. Most of the information regarding human pharmacokinetics of new opioids is based on toxicological case reports and the data on concentrations of new opioids in human blood are scarce. The interpretation of results usually requires a comparison to previously published cases; therefore, a referenced compilation of previously published concentration data would be useful. The data were collected by searching the PubMed and Scopus databases and by using the Google search engine. All the available data from articles and reports that measured new opioid concentrations in plasma, serum, or whole blood were included in the data analysis. The presented tables list the observed concentrations in fatal and nonfatal cases involving 37 novel synthetic opioids. Blood levels of new opioids are extremely difficult to interpret. Low blood concentrations of these substances do not rule out acute poisoning as their high potency creates a risk of respiratory depression even at low doses. Opioid tolerance, frequent presence of other drugs, and additional diseases make it impossible to define concentration ranges, especially the minimum fatal concentrations. This report provides quick access to the source articles quantifying novel synthetic opioids.
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Purpose A detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presented. Method Peer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse. Results In terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored. Conclusions International early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration.
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In this case report, we present an evaluation of the distribution of postmortem concentrations of 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) in a fatality attributed principally to the drug. A man who had a history of drug abuse was found unresponsive and not breathing on his bed. Drug paraphernalia, indicating drug insufflation, was located in the decedent's room. Toxicology screening tests in peripheral blood initially identified U-47700 using an alkaline drug screen with gas chromatography-mass spectrometry (GC-MS) following solid-phase extraction. It was subsequently confirmed and quantitated by GC-MS-specific ion monitoring analysis following liquid-liquid extraction. The U-47700 peripheral blood concentration was quantitated at 190 ng/mL compared to the central blood concentration of 340 ng/mL. The liver concentration was 1,700 ng/g, the vitreous was 170 ng/mL, the urine was 360 ng/mL and the gastric contained only a trace amount (<1 mg). Other drugs detected in peripheral blood were alprazolam (0.12 mg/L), nordiazepam (<0.05 mg/L), doxylamine (0.30 mg/L), diphenhydramine (0.14 mg/L), ibuprofen (2.4 mg/L), salicylic acid (<20 mg/L) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (2.4 ng/mL). The cause of death was certified as acute U-47700 and alprazolam abuse, and the manner of death was certified as accident.
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With the issuance of this final order, the Administrator of the Drug Enforcement Administration maintains the placement of the substances butyryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylbutanamide) and U–47700 (3,4-dichloro-N-[2- (dimethylamino)cyclohexyl]-Nmethylbenzamide), including their isomers, esters, ethers, salts, and salts of isomers, esters and ethers, in schedule I of the Controlled Substances Act. This scheduling action discharges the United States obligations under the Single Convention on Narcotic Drugs (1961). This action continues to impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, butyryl fentanyl and U– 47700.
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Recently, it has been documented that there has been a rise in synthetic opioid abuse. Synthetic opioids are compounds that were created to act as agonists for the opioid receptors. Like synthetic cannabinoids, most of these compounds were created by research groups or pharmaceutical companies in an attempt to find compounds that have medicinal use. Synthetic opioids have severe health implications when abused that can include hospitalization and death. Due to the high potency and the low dose required to produce the desired effects for these compounds, it was hypothesized that they may not be detectable in human performance case samples. However, this report documents a male driver who was involved in a single-vehicle incident. First responders treated the subject with naloxone as opioid drug impairment was suspected and he was transported to the local emergency room. The subject consented to a blood draw for a driving under the influence (DUI) investigation. Initial routine testing identified alprazolam at 55 ng/mL and fentanyl at less than 0.5 ng/mL. Further testing using a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay, confirmed the presence of carfentanil, furanyl fentanyl, para-fluoroisobutyryl fentanyl, U-47700 and its metabolite. To the author's knowledge, this is the first report of a DUI cases where carfentanil, U-47700 and other synthetic opioids were confirmed and described in a human performance blood sample. This case demonstrates the need to supplement routine toxicological analyses with a sensitive methodology that can detect synthetic opioids in human performance cases where opioid use may be implicated.
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Background U-47700 is a synthetic opioid developed by The Upjohn Company in the 1970s, which has recently appeared in the news and medical literature due to its toxicity. Currently, there are no clinical trial data assessing the safety of U-47700. Objective To describe the signs and symptoms of ingestion, laboratory testing, and treatment modalities for U-47700 intoxication. Discussion We searched PubMed, Embase, Web of Science, and EBSCO for articles using the term “U-47700” and “47700.” The following inclusion criteria were used: had to be in English; full text; must involve humans; must be either a randomized control trial, prospective trial, retrospective analysis, case series, or case report; and must include clinical findings at presentation. We identified and extracted data from relevant articles. Ten relevant articles were included with 16 patients. Patients that died after overdose with U-47700 typically presented to the hospital with pulmonary edema. Patients who survived an overdose presented with decreased mental status and decreased respiratory rate suggestive of an opioid toxidrome. Patients also commonly had tachycardia. Immunoassays failed to identify U-47700, and the identification of U-47700 required the use of chromatographic and spectral techniques. Conclusion We report the first clinical review of U-47700 intoxication.
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The Administrator of the Drug Enforcement Administration is issuing this final order to temporarily schedule the synthetic opioid, 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (also known as U-47700), and its isomers, esters, ethers, salts and salts of isomers, esters and ethers, into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act. This action is based on a finding by the Administrator that the placement of U-47700 into schedule I of the Controlled Substances Act is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle, U-47700.
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Novel psychoactive substances (NPS) represent significant analytical and interpretive challenges to forensic and clinical toxicologists. Timely access to case reports and reports of adverse incidents of impairment or toxicity is imperative to clinical diagnosis and treatment, as well as to interpretation of forensic results. Delays in identifying the presence of a novel intoxicating agent have significant consequences for public health and public safety. Adverse effects of intoxications with novel cannabinoids, stimulants, hallucinogens, benzodiazepines and opioids spanning January 2013 through December 2016 as reported in emergency departments, death investigations, impaired driving cases and other forensic contexts are the subject of this review. Discussion of the chemistry, pharmacology and adverse events associated with novel drug classes is summarized and described within. Adverse effects or symptoms associated with ingestion of more than 45 NPS have been abstracted and summarized in tables, including demographics, case history, clinical or behavioral symptoms, autopsy findings and drug confirmations with quantitative results when provided. Based on these findings and gaps in the available data, we provide recommendations for future toxicological testing of these evolving substances. These include development and management of a national monitoring program to provide real-time clinical and toxicological data, confirmed analytically, on emerging drugs and their known toxidromes and side effect profiles. Increased efforts should be made to analytically confirm the agents responsible for clinical intoxications involving adverse events in emergency department admissions or hospitalizations. Evidence-based community preparedness among analytical laboratories gained through active communication and sharing of toxicological findings and trends in NPS is imperative to assist in enabling early detection of new drugs in forensic and clinical populations.
Article
Following series of synthetic cannabinoid and synthetic cathinone derivatives, the illicit drug market has begun to see increased incidence of synthetic opioids including fentanyl and its derivatives, and other chemically unrelated opioid agonists including AH-7921 and MT-45. Among the most frequently encountered compounds in postmortem casework have been furanyl fentanyl (N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylfuran-2-carboxamide, Fu-F) and U-47700 (trans-3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)-N-methylbenzamide). Both drugs have been reported to be present in the heroin supply and to be gaining popularity among recreational opioid users, but were initially developed by pharmaceutical companies in the 1970s as candidates for development as potential analgesic therapeutic agents. A method was developed and validated for the analysis of U-47700, U-50488 and furanyl fentanyl in blood specimens. A total of 20 postmortem cases, initially believed to be heroin or other opioid-related drug overdoses, were submitted for quantitative analysis. The analytical range for U-47770 and U-50488 was 1-500 and 1-100 ng/mL for furanyl fentanyl. The limit of detection was 0.5 ng/mL for all compounds. Within the scope of the method, U-47700 was the only confirmed drug in 11 of the cases, 5 cases were confirmed for both U-47700 and furanyl fentanyl, and 3 cases were confirmed only for furanyl fentanyl. The mean and median blood concentrations for U-47700 were 253 ng/mL (±150) and 247 ng/mL, respectively, range 17-490 ng/mL. The mean and median blood concentrations for furanyl fentanyl were 26 ng/mL (±28) and 12.9 ng/mL, respectively, range 2.5-76 ng/mL. Given the widespread geographical distribution and increase in prevalence in postmortem casework, toxicology testing should be expanded to include testing for "designer opioids" in cases with histories consistent with opioid overdose but with no traditional opioids present or insufficient quantities to account for death.
Article
Background: In the last decade there has been a worldwide surge in the recreational abuse of novel psychoactive substances, particularly amphetamine derivatives and synthetic cannabinoids. Synthetic opioids such as AH-7921, MT-45, and U-47700, with structures distinct from those ever used therapeutically or described recreationally, have also recently emerged. Case details: We report a patient who suffered respiratory failure and depressed level of consciousness after recreationally using a novel synthetic opioid labeled U-47700. A single dose of naloxone administered by paramedics completely reversed his opioid poisoning. Comprehensive laboratory analysis confirmed the presence of a novel synthetic opioid and excluded other drugs. The drug used appeared to have caused a false positive benzodiazepine result on the initial urine drugs of abuse panel. Conclusion: The case we describe of toxicity from the synthetic opioid labeled U-47700 highlights the emerging trend of novel synthetic opioid abuse.
Article
The search for synthetic opioids as alternatives to opium-based derivatives has provided an important impulse to drug development around the globe. An important goal in the systematic evaluation of new drug candidates is the identification of compounds that provide a more favorable side-effect profile, which includes reduced dependence-producing properties and abuse liability. A rich source of information about these research efforts can be found in the scientific literature. However, the exploration of these important discoveries has also been increasingly mined by largescale producers of these materials, which are then offered for sale. These so-called ‘research chemicals’ or new psychoactive substances (NPS)[1] have created challenges to policy makers, clinicians, and law enforcement around the world.[2] Recent examples of synthetic opioids that emerged as NPS on the market, and which were associated with severe cases of adverse effects, include 3,4-dichloro-N- {[1-(dimethylamino)cyclohexyl]methyl}benzamide (AH-7921), 1-cyclohexyl-4-(1,2- diphenylethyl)piperazines (MT-45) and N-phenyl-N-[1-(2-phenylethyl)piperidin-4- yl]acetamide (acetylfentanyl), respectively (Figure 1). Following the recommendation provided by the World Health Organization’s Expert Committee on Drug Dependence (ECDD),[3] AH-7921 was placed in Schedule I of the 1961 Single Convention, as amended by the 1972 Protocol in 2015.[4] Furthermore, ECDD’s recommendation to place MT-45 into Schedule I and acetylfentanyl in Schedules I and IV of the same Convention[5] have been recently confirmed by the Commission on Narcotic Drugs.[6] -Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) (Figure 1) has recently emerged on the market and can be purchased from various Internet retailers and is a structural isomer of AH-7921 (Figure 1). The preparation of U- 47700 and other derivatives was disclosed by the Upjohn Company in the 1970s[7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself.[8,9] The presence of two chiral centres gives rise to a cis- and trans- racemic mixture with the trans-form being advertised for sale. Binding studies also revealed that U-47700 displayed an appreciable selectivity for the μ-opioid receptor over the −opioid receptor.[10,11] A variety of cyclohexyl trans-1,2-diamines have been found to be potent analgesics and the vicinal 1,2-diamine pattern has provided access to a large range of substances with diverse biological activities.[12-14] Since U-47700 did not progress to clinical trials, there is no direct clinical information pertaining to its effects. Keeping in mind the various limitations that may be associated with descriptions obtained from self-reporting users, its effects have been described with various positive and negative symptoms but appeared to be essentially comparable to other opioids. Specifically, euphoria was reported in individuals, sometimes being short-lived, as well as general lift in mood with these desired effects being experienced in waves. The negative effects were also opioid based, including nausea with some users describing respiratory depression. For some users, U-47700 had a shorter duration of action and the urge to keep re-dosing was stated as being very high.
Emerging Threat Reports: Mid-Year 2018
  • Drug Enforcement Administration
3,4-Difluoro-U-47700
  • Krotulski
Methylenedioxy-U-47700
  • Krotulski
Fentanyl in Chicago - By the Numbers
  • DEA Intelligence Program - Chicago Field Division
Reports of adverse events associated with use of novel psychoactive substances
  • B K Logan
  • A L A Mohr
  • M Friscia
  • A J Krotulski
  • D M Papsun
  • S L Kacinko
Logan, B.K., Mohr, A.L.A., Friscia, M., Krotulski, A.J., Papsun, D.M., Kacinko, S.L., et al. (2017) Reports of adverse events associated with use of novel psychoactive substances, 2013-2016: a review. Journal of Analytical Toxicology, 41, 573-610. 10.1093/jat/bkx031
Emerging Threat Reports: Mid-Year
Drug Enforcement Administration. (2018) Emerging Threat Reports: Mid-Year 2018. https://ndews.umd.edu/sites/ndews.umd.edu/files/deaemerging-threat-report-2018-mid-year.pdf (accessed Jun 1, 2020).